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Catheterization Conference October 27, 2011 Anit Mankad, MD. Ivabradine: Is there a cardiovascular benefit to pure heart rate reduction?. 1. By Harlan Jay Ellison (1965) “Heart Beat Hypothesis”. 2. Overview. Beta Blockers Activity, impact, intolerance
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Catheterization Conference • October 27, 2011 • Anit Mankad, MD Ivabradine: Is there a cardiovascular benefit to pure heart rate reduction? 1
By Harlan Jay Ellison (1965) • “Heart Beat Hypothesis” 2
Overview • Beta Blockers • Activity, impact, intolerance • Adrenergic (sympathetic) activity • If current and “Funny” Channels • Ivabradine • Early trials • BEAUTIFUL and SHIFT trials • Current indications outside the U.S. • Future considerations 3
Case • 55 yo WM, PMH history of CAD s/p previous PCI, Ischemic cardiomyopathy, EF 35%, Severe COPD with frequent use of inhalers, comes to your clinic for follow-up, describing low grade stable angina for months (since PCI). • On metoprolol 6.25mg bid, amlodipine 10mg, asa, plavix, statin, ISMN 60mg • BP 110/60, HR 88 at rest. • What can we offer him? 4
Elevated Resting Heart Rate • Accelerates production of atherosclerosis (Int J Cardiol 2008;126:302-12) • Associated with coronary plaque disruption (Circulation 2001;126:1477-82) • Framingham Study • progressive increase in all cause and cardiovascular mortality in relation to antecedent HR (Am Heart J 1987; 113:1489-94) • Continuous increase in death rates in survivors of Acute MI • starting at HR > 70(J Am Coll Cardiol 2007;50:823-30) 5
Mechanism of Consequences of Elevated Resting Heart Rate • Increases myocardial oxygen demand • Decreases myocardial perfusion by reducing diastolic perfusion time (Circulation 1979;60:164-9) • Causes vasoconstriction of diseased coronary arteries • Sambuceti et al. (Circulation. 1997; 95: 2652-9) • 10 patients found to have LAD stenosis (mean 80±5%) vs 7 controls with atypical chest pain, no significant CAD. • Pacer lead in RA, flow wire to calculate coronary resistance index • AdenosinePacing (increments of 20bpm increase) Adenosine 6
. Sambuceti G et al. Circulation 1997;95:2652-2659 7
Heart Rate in Cardiovascular Outcomes • Diaz et al. • 25,000 patients who had cardiac cath requests for suspected or proven CAD • Divided heart rate into quintiles • Multivariable Cox PH models • Adjusted for beta-blockers use • As well as smoking, DM, HTN, gender, age, EF, antiplatelet and lipid agents 8
Beta-Adrenoceptors • Endogenous catecholamines • activate B-receptors • (Adenylate Cyclase) • Increased cAMP • Increased Ca++ influx Inotropic Chronotropic 14
Beta Blockers (BB) • B1negative chronotropy and inotropy • AV conduction delay • Reduced atrial and ventricular arrythmias • B2Bronchoconstriction • Peripheral unopposed alpha constriction • Decrease glycogenolysis • (contribute to hypoglycemic events) • Other antagonize release of renin • reduces intraocular pressures 15
Impact of BB • Acute MI • Norwegian Multicenter Study Group Timolol * • CAPRICORN † • ISIS-1 ‡ • CHF • COPERNICUS £ • MERIT-HF € 16
Intolerence of BB • Side effects • Bronchoconstriction, AV delay, hypoglycemia • Weight gain, depression, fatigue • BB may not be tolerated in high enough doses to attain heart rates below 70bpm • Acute setting (Acute MI, or CHF), the negative inotropic effect could be deleterious • This has been shown in dogs (Eur Heart J (2004) 25 (7): 579-586 17
If Current • H.F.Brown (1979) • means for acceleration of diastolic depolarization (heart rate) in adrenergic response • Sinoatrial Node • NA-K inward current • Regulated by the Funny Channel • cAMP 19
Ivabradine • Specifically binds the Funny channel • Reduces the slope for diastolic depolarization • Prolongs diastolic duration • Does not alter… • Ventricular repolarization • Myocardial contractility • Blood pressure 22
Ivabradine • 2005--Approved by the European Medicine Agency • Trade: Procoralan, Coralan (India), Corlentor (Italy) • 2.5mg, 5mg, 7.5mg. Two times a day • Side Effects (%) • Teratogenic • Pregnancy • Breast feeding 23
Heart rate Reduction during Exercise-inducedMyocardial Ischemia and Stunning • 5 dogs with implanted LCx occluder, ultrasound crystals (LV wall thickness), and pacer • Ivabradine vs atenolol vs saline • Administered before or after 10min on treadmill • Paced at 150bpm for 6 hours 25
Administration BEFORE Onset of Exercise Saline (full circles) Ivabradine (open circles) Atenolol (open triangles) *P<0.05: atenolol and ivabradine significantly different from saline. Monnet X et al. Eur Heart J 2004;25:579-586 26
Administration BEFORE Onset of Exercise AND PACED Saline (full circles) Ivabradine (open circles) Atenolol (open triangles) *P<0.05: atenolol and ivabradine significantly different from saline. †P<0.05: atenolol significantly different from ivabradine. Monnet X et al. Eur Heart J 2004;25:579-586 27
Administration AFTER Onset of Exercise Saline (full circles) Ivabradine (open circles) Atenolol (open triangles) *P<0.05: atenolol and ivabradine significantly different from saline. †P<0.05: atenolol significantly different from ivabradine. Monnet X et al. Eur Heart J 2004;25:579-586 28
Administration AFTER Onset of Exercise AND PACED Saline (full circles) Ivabradine (open circles) Atenolol (open triangles) *P<0.05: atenolol and ivabradine significantly different from saline. †P<0.05: atenolol significantly different from ivabradine. Monnet X et al. Eur Heart J 2004;25:579-586 29
Ivabradine Trials • Reduces atherosclerosis (Circ 2008;117:2377-87) • Decreases vascular oxidative stress • Improves endothelial function • Increases exertional tolerance and time to ischemia in patients with > 3 months angina (Circ 2003;107:817-23) • Non-inferior to Atenolol (Eur Heart J 2005;26:2529-36) • Exercise tolerance, time to angina or ischemia • Non-inferior to Amlodipine (Drugs 2007;67(3):393-405) 30
BEAUTIFUL Trial • Randomized, double-blinded, placebo controlled • 781 centers, 33 countries • 11,000 subjects (between 2005 and 2007) • Male (98%), Caucasian (83%), HR>60, EF<40% • CAD and on optimal medical management • 87% on BB, 89% on ACE/ARBs, 27% Aldo antagonists • Ivabradine vs placebo, followed for 3 years • 5mg bid, if HR >60 at 2 weeks, increase to 7.5mg • Primary endpoint was a composite of CV death and hospitalizations for MI or CHF • Subgroup analysis: HR>70 (5,400) 31
What Can We Conclude from the BEAUTIFUL Trial? • While there was no difference total cardiovascular mortality • Ivabradine use appears to be a benefit in reducing readmissions due to coronary artery disease (when resting heart rate > 70) • Acute Myocardial Infarction • Coronary Revascularization 38
SHIFT Trial • Randomized, double-blinded, placebo controlled • 6,500 subjects • Male (76%), Caucasian (89%) • Class II – IV heart failure, EF<35%, HR>70bpm • Admission for heart failure in the previous 2 months • On optimal medical management • 90% on BB, 84% on ACE/ARBs, 60% Aldo antagonists • Ivabradine vs placebo, followed for 3 years • Primary endpoint: composite of CV death or hospital admission for heart failure. 39
What Can We Conclude from the SHIFT Trial? • In patients with all-cause cardiomyopathy (EF<35%), and heart rates > 70bpm, • While there was no difference total cardiovascular mortality, • Ivabradine reduces… • Mortality due to Heart Failure • Heart failure admissions 48
Current IndicationsEuropean Medicines Agency • “Treatment of symptoms of long-term stable angina in adults (aged over 18 years) with coronary artery disease who have normal sinus rhythm. • It can be used in the following groups • Patients who cannot take or tolerate beta-blockers • Patients whose disease is not controlled with beta-blockers and whose heart rate is above 60bpm.” 49
Future Considerations • Use of Ivabradine in the acute setting • Acute myocardial infarction • Upon onset of congestive heart failure? • Diastolic heart failure? 50